Diaminopyrroloquinazolines compounds as protein tyrosine phosphatase inhibitors

Abstract

This invention relates to diaminopyrroloquinazoline compounds which are useful for inhibiting protein tyrosine phosphatases, particularly PTP1B, and are useful for lowering blood glucose concentrations in mammals.

1. A compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein,
 R1 is selected from the group consisting of lower alkyl, aryl lower alkyl, acetyl, aryl lower alkoxy lower alkyl and mono- or di-hydroxy substituted lower alkyl; 
 R2 is selected from the group consisting of hydrogen, lower alkyl, aryl lower alkyl, acetyl, mono- or di-hydroxy substituted lower alkyl and aryl lower alkoxy lower alkyl; 
 Ra is selected from the group consisting of hydrogen, aryl lower alkyl, lower alkyl, lower alkoxy, mono- or di-hydroxy substituted lower alkyl and 
 
       
         
           
           
               
               
           
         
         R 10  is selected from hydrogen and 
       
       
         
           
           
               
               
           
         
         Rb, Rc, Rd, Re and Rf are individually selected from the group consisting of hydrogen, perfluro-lower alkyl, halogen, lower alkyl substituted aryl lower alkyl, lower alkoxy, aryl lower alkoxy and 
       
       
         
           
           
               
               
           
         
         R 11  is selected from hydrogen, lower alkyl and aryl; 
         p is an integer from 0 to 1; and 
         x and y are individually integers from 0 to 4, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       2. The compound of  claim 1  wherein
 R1 is selected from the group consisting of methyl, ethyl, benzyl, acetyl, 2,3-dihydroxypropyl, 3-hydroxypropyl and 2-benzyloxyethyl; 
 R2 is selected from the group consisting of hydrogen, methyl, ethyl, benzyl, and acetyl; 
 Ra is selected from the group consisting of hydrogen, methyl, hydroxyethyl, 2-benzyloxy-ethyl and 2-[4-difluorophosphono-methyl]-benzyloxy]-ethyl; 
 Rb is selected from the group consisting of hydrogen, methyl, methoxy, phenoxy and trifluoromethyl; 
 Rc and Rd are each independently selected from hydrogen and trifluoromethyl; 
 Re is selected from the group consisting of hydrogen, chlorine and trifluoromethyl; and 
 Rf is selected from hydrogen and methyl. 
 
     
     
       3. A compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein,
 R 5  is selected from the group consisting of hydrogen, lower alkyl, aryl lower alkyl, mono- or di-hydroxy substituted lower alkyl and aryl lower alkoxy loweralkyl; 
 R 6  is selected from the group consisting of lower alkyl, aryl lower alkyl, mono- or di-hydroxy substituted lower alkyl and aryl lower alkoxy lower alkyl; 
 R 7  is selected from the group consisting of hydrogen, lower alkyl, mono- or di-hydroxy substituted lower alkyl, and 
 
       
         
           
           
               
               
           
         
         R 10  is selected from hydrogen and 
       
       
         
           
           
               
               
           
         
         R 8  and R 9  are individually selected from the group consisting of hydrogen, perfluoro-lower alkyl, halogen, lower alkyl substituted aryl lower alkyl, lower alkyl, aryl lower alkoxy and 
       
       
         
           
           
               
               
           
         
         R 11  is selected from hydrogen, aryl and lower alkyl; 
         p is an integer from 0 to 1; and 
         x and y are individually integers from 0 to 4, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       4. The compound of  claim 3  wherein
 R 5  is selected from hydrogen and lower alkyl; 
 R 6  is lower alkyl; and 
 R 8  and R 9  are selected from perfluoroloweralkyl and hydrogen with at least one or R 8  and R 9  being perfluoroloweralkyl. 
 
     
     
       5. The compound of  claim 4  wherein R 7  is selected from hydrogen and lower alkyl. 
     
     
       6. The compound of  claim 5  wherein said compound is 7,N1,N1-trimethyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt. 
     
     
       7. The compound of  claim 5  wherein said compound is N1,N1-diethyl-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt. 
     
     
       8. The compound of  claim 5  wherein said compound is 7-methyl-N1,N1-dipropyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluor-acetic acid salt. 
     
     
       9. The compound of  claim 5  wherein said compound is 7,N1,N1-trimethyl-6-(4-trifluoromethyl-phenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine. 
     
     
       10. The compound of  claim 5  wherein said compound is 7,N1-dimethyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt. 
     
     
       11. The compound of  claim 4  wherein R 7  is mono- or di-hydroxy substituted lower alkyl. 
     
     
       12. The compound of  claim 11  wherein said compound is 2-[3-amino-1-dimethylamino-6-(2-trifluoromethyl-phenyl)-pyrrolo[3,2-f]quinazolin-7-yl]-ethanol trifluoro-acetic acid salt. 
     
     
       13. The compound of  claim 3  wherein R 5  is hydrogen or mono- or di-hydroxy substituted lower alkyl, R 6  is mono- or di-hydroxy substituted lower alkyl, and R 8  and R 9  are independently selected from perfluoroloweralkyl and hydrogen with at least one of said R 8  and R 9  being perfluoroloweralkyl. 
     
     
       14. The compound of  claim 13  wherein said compound is 3-[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo[3,2-f]quinazolin-1-ylamino]-propan-1-ol trifluoro-acetic acid salt. 
     
     
       15. The compound of  claim 13  wherein said compound is 3-[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo[3,2-f]quinazolin-1-ylamino]-propane-1,2-diol trifluoro-acetic acid salt. 
     
     
       16. The compound of  claim 13  wherein said compound is 2-[[3-amino-7-methyl-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo[3,2-f]quinazolin-1-yl]-(2-hydroxy-ethyl)-amino]-ethanol trifluoro-acetic acid salt. 
     
     
       17. The compound of  claim 4  wherein R 7  is 
       
         
           
           
               
               
           
         
       
       and R 10 , x and y are as above. 
     
     
       18. The compound of  claim 17  wherein said compound is [(4-{2-[3-amino-1-dimethylamino-6-(2-trifluoromethyl-phenyl)-pyrrolo[3,2-f]quinazolin-7-yl]-ethoxymethyl}-phenyl)-difluoro-methyl]-phosphonic acid. 
     
     
       19. The compound of  claim 17  wherein said compound is produced 7,N1-bis-(2-benzyloxy-ethyl)-6-(2-trifluoromethyl-phenyl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt. 
     
     
       20. The compound of  claim 3  wherein one of R 8  or R 9  is selected from 
       
         
           
           
               
               
           
         
       
       and lower alkoxy, and p is as above. 
     
     
       21. The compound of clam  20  wherein said compound is 6-(2-methoxy-phenyl)-7,N1-dimethyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt. 
     
     
       22. The compound of  claim 20  wherein said compound is 6-(2-methoxy-phenyl)-7,N1,N1-trimethyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt. 
     
     
       23. The compound of  claim 3  wherein one of R 8  and R 9  is lower alkyl. 
     
     
       24. The compound of  claim 23  wherein said compound is 6-(2,6-dimethyl-phenyl)-7,N1,N1-trimethyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt. 
     
     
       25. The compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein,
 {circle around (P)} is a 5 or 6 membered heteroaromatic ring containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; 
 R 5  is selected from the group consisting of hydrogen, lower alkyl, aryl lower alkyl, mono- or di-hydroxy substituted lower alkyl, and aryl lower alkoxy loweralkyl; 
 R 6  is selected from the group consisting of lower alkyl, aryl lower alkyl, mono- or di-hydroxy substituted lower alkyl, and aryl lower alkoxy lower alkyl; 
 R 7  is selected from the group consisting of hydrogen, aryl lower alkyl, lower alkyl, lower alkoxy, mono- or di-hydroxy substituted lower alkyl, and 
 
       
         
           
           
               
               
           
         
         R 10  is selected from hydrogen and 
       
       
         
           
           
               
               
           
         
         R 8  and R 9  are individually selected from the group consisting of hydrogen, perfluoro-lower alkyl, halogen, lower alkyl substituted aryl lower alkyl, lower alkyl, aryl lower alkoxy and 
       
       
         
           
           
               
               
           
         
         R 11  is selected from the group consisting of hydrogen, lower alkyl and aryl; 
         p is an integer from 0 to 1; and 
         x and y are individually integers from 0 to 4, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       26. The compound of  claim 25  wherein {circle around (P)} is a 5 or 6 membered heteroaromatic ring containing a sulfur hetero atoms as the only heteroaromatic atom in said ring. 
     
     
       27. The compound of  claim 26  wherein
 R 8  and R 9  are selected from hydrogen and lower alkyl; 
 R 5  is selected from the group consisting of hydrogen, lower alkyl and mono- or di-hydroxy substituted lower alkyl; and 
 R 6  is selected from lower alkyl and mono- or di-hydroxy substituted lower alkyl. 
 
     
     
       28. The compound of  claim 27  wherein said compound is 2-(3-amino-7-methyl-6-thiophen-2-yl-7H-pyrrolo[3,2-f]quinazolin-1-ylamino)-ethanol trifluoro-acetic acid salt. 
     
     
       29. The compound of  claim 27  wherein said compound is 2-[3-amino-7-methyl-6-(5-methyl-thiophen-2-yl)-7H-pyrrolo[3,2-f]quinazolin-1-ylamino]-ethanol trifluoro-acetic acid salt. 
     
     
       30. The compound of  claim 27  wherein said compound is 3-(3-amino-7-methyl-6-thiophen-2-yl-7H-pyrrolo[3,2-f]quinazolin-1-ylamino)-propan-1-ol trifluoro-acetic acid salt. 
     
     
       31. The compound of  claim 27  wherein said compound is 7,N1-dimethyl-6-thiophen-2-yl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt. 
     
     
       32. The compound of  claim 27  wherein said compound is 7,N1,N1-trimethyl-6-thiophen-2-yl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine. 
     
     
       33. The compound of  claim 27  wherein said compound is 7,N1-dimethyl-6-(5-methyl-thiophen-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine. 
     
     
       34. The compound of  claim 27  wherein said compound is 7-ethyl-N1-methyl-6-thiophen-2-yl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt. 
     
     
       35. The compound of  claim 27  wherein said compound is 7-ethyl-N1,N1-dimethyl-6-thiophen-2-yl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt. 
     
     
       36. The compound of  claim 27  wherein said compound is N1,N1-diethyl-7-methyl-6-thiophen-2-yl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt. 
     
     
       37. The compound of  claim 26  wherein
 R 8  and R 9  are independently selected from the group consisting of hydrogen, lower alkoxy, and aryl lower alkoxy with at least one of R 8  and R 9  being other than hydrogen; 
 R 5  is selected from the group consisting of hydrogen, lower alkyl and mono- or di-hydroxy substituted lower alkyl; and 
 R 6  is selected from lower alkyl and mono- or di-lower hydroxy substituted lower alkyl. 
 
     
     
       38. The compound of  claim 37  wherein said compound is 6-(5-methoxy-thiophen-2-yl)-7,N1,N1-trimethyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine. 
     
     
       39. The compound of  claim 37  wherein said compound is 6-(5-methoxy-thiophen-2-yl)-7,N1-dimethyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine. 
     
     
       40. The compound of  claim 37  wherein said compound is 6-(4-methoxy-thiophen-2-yl)-7,N1,N1-trimethyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine. 
     
     
       41. The compound of  claim 37  wherein said compound is 6-(4-methoxy-thiophen-2-yl)-7,N1-dimethyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine. 
     
     
       42. The compound of  claim 25  wherein
 {circle around (P)} is a 5 or 6 membered heteroaromatic ring containing an oxygen atom as the only hetero atom. 
 
     
     
       43. The compound of  claim 42  wherein
 R 5  is selected from hydrogen and lower alkyl; and 
 R 6  is lower alkyl. 
 
     
     
       44. The compound of  claim 43  wherein said compound is 6-furan-3-yl-7,N1,N1-trimethyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine. 
     
     
       45. The compound of  claim 43  wherein said compound is 6-furan-2-yl-7,N1-dimethyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine trifluoro-acetic acid salt. 
     
     
       46. The compound of  claim 25  wherein {circle around (P)} is a 5 or 6 membered heteroaromatic ring containing a nitrogen atom as the only hetero atom. 
     
     
       47. The compound of  claim 46  wherein
 one of R 8  and R 9  is hydrogen and the other is selected from hydrogen, lower alkyl and 
 
       
         
           
           
               
               
           
         
       
       wherein
 R 11  is selected from aryl and lower alkyl; and 
 R 5  and R6 are lower alkyl. 
 
     
     
       48. The compound of  claim 47  wherein said compound is 2-(3-amino-1-dimethylamino-7-methyl-7H-pyrrolo[3,2-f]quinazolin-6-yl)-pyrrole-1-carboxylic acid tert-butyl ester. 
     
     
       49. The compound of  claim 25  wherein {circle around (P)} is a 5 or 6 membered heteroaromatic ring containing two heteroatoms. 
     
     
       50. The compound of  claim 49  wherein R 8  and R 9  are independently selected from the group consisting of lower alkyl, hydrogen and lower alkoxy. 
     
     
       51. The compound of  claim 50  wherein said compound is 6-(2,4-dimethoxy-pyrimidin-5-yl)-7,N1,N1-trimethyl-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine. 
     
     
       52. A pharmaceutical composition comprising one or more compounds of the formula: 
       
         
           
           
               
               
           
         
       
       wherein,
 R1 is selected from the group consisting of lower alkyl, aryl lower alkyl, acetyl, aryl lower alkoxy lower alkyl, and mono- or di-hydroxy substituted lower alkyl; 
 R2 is selected from the group consisting of hydrogen, lower alkyl, aryl lower alkyl, acetyl, mono- or di-hydroxy substituted lower alkyl and aryl lower alkoxy lower alkyl; 
 Ra is selected from the group consisting of hydrogen, aryl lower alkyl, lower alkyl, lower alkoxy, mono- or di-hydroxy substituted lower alkyl and 
 
       
         
           
           
               
               
           
         
         R 10  is selected from hydrogen and 
       
       
         
           
           
               
               
           
         
         R 8  and R 9  are individually selected from the group consisting of hydrogen, perfluoro-lower alkyl, halogen, lower alkyl substituted aryl lower alkyl, lower alkyl, aryl lower alkoxy and 
       
       
         
           
           
               
               
           
         
         R 11  is selected from hydrogen, lower alkyl and aryl; 
         p is an integer from 0 to 1; and 
         x and y are individually integers from 0 to 4, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       53. A pharmaceutical composition comprising one or more compounds of the formula: 
       
         
           
           
               
               
           
         
       
       wherein,
 R 5  is selected from the group consisting of hydrogen, lower alkyl, aryl lower alkyl, mono- or di-hydroxy substituted lower alkyl, and aryl lower alkoxy loweralkyl; 
 R 6  is lower alkyl, aryl lower alkyl, mono- or di-hydroxy substituted lower alkyl, and aryl lower alkoxy lower alkyl; 
 R 7  is hydrogen, lower alkyl, mono- or di-hydroxy substituted lower alkyl, and 
 
       
         
           
           
               
               
           
         
         R 10  is selected from hydrogen and 
       
       
         
           
           
               
               
           
         
         R 8  and R 9  are individually selected from the group consisting of hydrogen, perfluoro-lower alkyl, halogen, lower alkyl substituted aryl lower alkyl, lower alkyl, aryl lower alkoxy, phenoxy, and 
       
       
         
           
           
               
               
           
         
         R 11 , is selected from hydrogen, aryl and lower alkyl; 
         p is an integer from 0 to 1; and 
         x and y are individually integers from 0 to 4, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       54. A method of treating diabetes comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein,
 R1 is selected from the group consisting of lower alkyl, aryl lower alkyl; acetyl, aryl lower alkoxy lower alkyl, and mono- or di-hydroxy substituted lower alkyl; 
 R2 is selected from the group consisting of hydrogen, lower alkyl, aryl lower alkyl, acetyl, mono- or di-hydroxy substituted lower alkyl, and aryl lower alkoxy lower alkyl; 
 Ra is selected from the group consisting of hydrogen, aryl lower alkyl, lower alkyl, lower alkoxy, mono- or di-hydroxy substituted lower alkyl and 
 
       
         
           
           
               
               
           
         
         R 10  is selected from hydrogen and 
       
       
         
           
           
               
               
           
         
         Rb, Rc, Rd, Re and Rf are individually selected from the group consisting of hydrogen, perfluro-lower alkyl, halogen, lower alkyl substituted aryl lower alkyl, lower alkoxy, aryl lower alkoxy and 
       
       
         
           
           
               
               
           
         
         R 11  is selected from hydrogen, lower alkyl and aryl; 
         p is an integer from 0 to 1; and 
         x and y are individually integers from 0 to 4, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       55. A method of treating diabetes comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein,
 R 5  is selected from the group consisting of hydrogen, lower alkyl, aryl lower alkyl, mono- or di-hydroxy substituted lower alkyl, and aryl lower alkoxy loweralkyl; 
 R 6  is selected from the group consisting of lower alkyl, aryl lower alkyl, mono- or di-hydroxy substituted lower alkyl, and aryl lower alkoxy lower alkyl; 
 R 7  is hydrogen, lower alkyl, mono- or di-hydroxy substituted lower alkyl, and 
 
       
         
           
           
               
               
           
         
         R 10  is selected from hydrogen and 
       
       
         
           
           
               
               
           
         
         R 8  and R 9  are individually selected from the group consisting of hydrogen, perfluoro-lower alkyl, halogen, lower alkyl substituted aryl lower alkyl, lower alkyl, aryl lower alkoxy, phenoxy and 
       
       
         
           
           
               
               
           
         
         R 11  is selected from hydrogen, aryl and lower alkyl; 
         p is an integer from 0 to 1; and 
         x and y are individually integers from 0 to 4, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       56. A pharmaceutical composition comprising one or more compounds of the formula: 
       
         
           
           
               
               
           
         
       
       wherein,
 {circle around (P)} is a 5 or 6 membered heteroaromatic ring containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; 
 R 5  is selected from the group consisting of hydrogen, lower alkyl, aryl lower alkyl, mono- or di-hydroxy substituted lower alkyl, and aryl lower alkoxy loweralkyl; 
 R 6  is selected from the group consisting of lower alkyl, aryl lower alkyl, mono- or di-hydroxy substituted lower alkyl, and aryl lower alkoxy lower alkyl; 
 R 7  is selected from the group consisting of hydrogen, aryl lower alkyl, lower alkyl, lower alkoxy, mono- or di-hydroxy substituted lower alkyl and 
 
       
         
           
           
               
               
           
         
         R 10  is selected from hydrogen and 
       
       
         
           
           
               
               
           
         
         R 8  and R 9  are individually selected from the group consisting of hydrogen, perfluoro-lower alkyl, halogen, lower alkyl substituted aryl lower alkyl, lower alkyl, aryl lower alkoxy and 
       
       
         
           
           
               
               
           
         
         R 11  is selected from the group consisting of hydrogen, lower alkyl and aryl; 
         p is an integer from 0 to 1; and 
         x and y are individually integers from 0 to 4, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
       57. A method of treating diabetes comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein,
 {circle around (P)} is a 5 or 6 membered heteroaromatic ring containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen; 
 R 5  is selected from the group consisting of hydrogen, lower alkyl, aryl lower alkyl, mono- or di-hydroxy substituted lower alkyl, and aryl lower alkoxy loweralkyl; 
 R 6  is selected from the group consisting of lower alkyl, aryl lower alkyl, mono- or di-hydroxy substituted lower alkyl, and aryl lower alkoxy lower alkyl; 
 R 7  is selected from the group consisting of hydrogen, aryl lower alkyl, lower alkyl, lower alkoxy, mono- or di-hydroxy substituted lower alkyl and 
 
       
         
           
           
               
               
           
         
         R 10  is selected from hydrogen and 
       
       
         
           
           
               
               
           
         
         R 8  and R 9  are individually selected from the group consisting of hydrogen, perfluoro-lower alkyl, halogen, lower alkyl substituted aryl lower alkyl, lower alkyl, aryl lower alkoxy and 
       
       
         
           
           
               
               
           
         
         R 11  is selected from the group consisting of hydrogen, lower alkyl and aryl; 
         p is an integer from 0 to 1; and 
         x and y are individually integers from 0 to 4 
       
       or a pharmaceutically acceptable salt thereof.